In a principal aspect, the present invention relates to calcium phosphate cements, their preparation, composition and physicochemical properties particularly as enhanced by fluoride materials.
Calcium phosphate cements (CPCs) have been the subject of considerable interest in the field of bone graft biomaterials. Such materials have been found to be biocompatible and osteoconductive. This leaves CPCs bio-resorption characteristics as one of the remaining important properties to be more fully understood and controlled in order to achieve optimum CPC-to-bone conversion.
CPCs of different compositions can form different end products such as hydroxyapatite (HA), octacalcium phosphate, and dicalcium phosphate dihydrate (DCPD), also known as brushite. An in vivo property of HA-forming CPCs is that the HA formed does not dissolve spontaneously in a normal physiological fluid environment, yet is resorbable under cell-mediated acidic conditions. Although DCPD is soluble in normal physiological fluids, studies have shown that resorption of DCPD-forming CPC is also essentially cell-mediated, mainly due to conversion of the DCPD to an apatitic phase in situ.
In this regard, studies on fluoride (F)-substituted hydroxyapatite (HA)-based biomaterials show that F can play useful roles in calcium phosphate-based bone grafts. F-substitute HA has been shown to promote bone formation in rat tibia [Inoue et al, 20051; Inoue 20102] and dog mandible [Sakae et al., 20033]. Studies using human osteoblast-like cells show that a low level F-substitution HA enhanced osteocalcin expression [Grzanna et al., 20034], and fluorapatite (FA)-collagen composites exhibited higher cell proliferation and differentiation [Yoon et al., 20055] compared to the F-free counterpart. A study in the patent literature [Yuan et al., 20106] claims that NaF-loaded tricalcium phosphate (TCP) ceramic exhibited osteoinductivity in a goat model. These findings suggest that fluoride may play a role in bone formation and therefore F-releasing bone graft materials may provide an added advantage. The noted references are incorporated herewith by reference. 1 Inoue M, Nagatsuka H, Tsujigiwa H, Inoue M, LeGeros R Z, Yamamoto T, Nagai N (2005). In vivo effect of fluoride-substituted apatite on rat bone. Dent Mater J 24:398-402.2 Inoue M, Rodriguez A P, Nagai N, Nagatsuka H, LeGeros R Z, Tsujigiwa H, Inoue M, Kishimoto E, Takagi S (2010). Effect of fluoride-substituted apatite on in vivo bone formation. J Biomater Appl March 10.3 Sakae T, Ookubo A, LeGeros R Z, Shimogoryo R, Sato Y, Lin S, Yamamoto H, Kozawa (2003). Bone formation induced by several carbonate- and fluoride containing apatite implanted in dog mandible. Key Engineering Materials vols 240-242:395-398.4 Grzanna M, LeGeros R Z, Polotsky A, Lin S, Hungerford D S, Frondoza C G (2003). Fluoride-substituted apatite support proliferation and expression of human osteoblast phenotype in vitro. Key Engineering Materials vols 240-242:695-698.5 Yoon B H, Kim H W, Lee S H, Bae C J, Koh Y H, Kong Y M, Kim H E (2005). Stability and cellular responses to fluorapatite-collagen composites. Biomaterials 26:2957-2963.6 Yuan H, de Bruijn J D, de Groot K (2010). Method of improving the osteoinductivity of calcium phosphate. Patent Application Publication# US2010/0003304 A1, January 7.
A number of patents on calcium phosphate cements (CPC) [Chow and Takagi, 19967, Chow and Takagi, 19998; Lin et al, 20029; Dickens, 200310; Khairoun et al, 200811] have disclosed the inclusion of F, in either a highly soluble form, e.g., sodium fluoride (NaF), or sparingly soluble form, e.g., calcium fluoride (CaF2), into the compositions. However, no attempts are understood to have been made to understand the amounts and forms of F that can be incorporated into the CPC product. Neither is there understood to be information on the properties of any F-containing CPCs. 7 Chow L C, Takagi S (1996). Self-setting calcium phosphate cements and methods for preparing and using them. U.S. Pat. No. 5,525,148, June 11.8 Chow L C, Takagi S (1999). Self-setting calcium phosphate cements and methods for preparing and using them. U.S. Pat. No. 5,954,867, September 21.9 Lin Jiin-Huey C, Ju Chien-Ping, Chen Wen-Cheng (2002). Process for producing fast-setting, bioresorbable calcium phosphate cements. U.S. Pat. No. 6,379,453, April 30.10 Dickens S (2003). Single solution bonding formulation. U.S. Pat. No. 6,649,669, November 18.11 Khairoun I, LeGeros R Z. Daculsi G, Bouler Jean-Michael, Guicheux J, Gauthier O (2008). Macroporous, resorbable and injectible calcium phosphate-based cements (MCPC) for bone repair, augmentation, regeneration, and osteoporosis treatment. U.S. Pat. No. 7,351,280, April 1.
Nonetheless such information is believed to be relevant since CPCs with different resorption rates may be especially suitable for different clinical applications. That is, for some clinical applications, specifically endodontic applications, such as root end fill, perforation repair, etc., it is desirable to have CPCs that are biocompatible and osteoconductive, yet non-bioresorbable in soft and hard tissues. Since in vivo resorption is a result of dissolution in a cell-mediated acidic environment, CPCs that form products that have little or practically no solubility in such acidic conditions can be expected to be essentially non-resorbable.
For example, literature suggests that fully or partially fluoridated HA materials have significantly lower solubility in acids. Thus, fluorapatite (FA)-forming CPCs can be expected to have much lower resorbability than HA-forming CPCs. As a consequence, development of FA-forming CPCs and their physicochemical properties as well as in vivo resorption characteristics are reasonable objectives in order to facilitate their utility. As a consequence, methods for preparation of fluoride containing CPC's and their associated physicochemical properties will enable useful therapeutic options, for example, with respect to clinical endodontic applications.